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PKCθ Synergizes with TLR-Dependent TRAF6 Signaling Pathway to Upregulate MUC5AC Mucin via CARMA1  [PDF]
Hirofumi Jono, Jae Hyang Lim, Haidong Xu, Jian-Dong Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031049
Abstract: CARD-containing MAGUK protein 1 (CARMA1) plays a crucial role in regulating adaptive immune responses upon T-cell receptor (TCR) activation in T cells. Its role in regulating host mucosal innate immune response such as upregulation of mucin remains unknown. Here we show that CARMA1 acts as a key signaling mediator for synergistic upregulation of MUC5AC mucin by bacterium nontypeable Haemophilus influenzae (NTHi) and phorbol ester PMA in respiratory epithelial cells. NTHi-induced TLR-dependent TRAF6-MKK3-p38 MAPK signaling pathway synergizes with PKCθ-MEK-ERK signaling pathway. CARMA1 plays a crucial role in mediating this synergistic effect via TRAF6, thereby resulting in synergistic upregulation of MUC5AC mucin. Thus our study unveils a novel role for CARMA1 in mediating host mucosal innate immune response.
Citrus jabara Extracts Suppress MUC5AC Mucin Production in Human Lung Epithelial Cells  [PDF]
Jun Iwashita, Naoki Iguchi, Akiko Takashima, Daisuke Watanabe, Kimihiko Sano, Masahiko Ishikuro, Keishi Hata, Jun Murata
Advances in Biological Chemistry (ABC) , 2017, DOI: 10.4236/abc.2017.73009
Abstract: In the human airway, the overproduction of MUC5AC mucin is a key feature of allergic asthma, and it induces airway narrowing and obstruction. The production of MUC5AC is regulated by several signals, but the mechanism is not completely understood. We investigated the effect of jabara, a citrus containing abundant flavonoids, on the regulation of MUC5AC production. When NCI-H292 human airway epithelial cells were cultured with jabara extracts, we found that the expression of Periodic acid-schiff stained mucin was suppressed with downregulated MUC5AC production. In human primary airway cells derived from asthmatic patients, MUC5AC production was also suppressed by jabara extracts. The treatment of cells with jabara extracts decreased ERK activation in NCI-H292 and in primary cells. These results show that jabara extracts contain some factors that suppress MUC5AC production and ERK activity and suggest that it will be useful for relieving asthma.
RNA interference suppression of mucin 5AC (MUC5AC) reduces the adhesive and invasive capacity of human pancreatic cancer cells
Sadaaki Yamazoe, Hiroaki Tanaka, Tetsuji Sawada, Ryosuke Amano, Nobuya Yamada, Masaichi Ohira, Kosei Hirakawa
Journal of Experimental & Clinical Cancer Research , 2010, DOI: 10.1186/1756-9966-29-53
Abstract: We used two MUC5AC expressing cell lines derived from human pancreatic cancer, SW1990 and BxPC3. Small-interfering (si) RNA directed against MUC5AC were used to assess the effects of MUC5AC on invasion and adhesion of pancreas cancer cells in vitro and in vivo. We compared parental cells (SW1990 and BxPC3) with MUC5AC suppressed cells by si RNA (si-SW1990 and si-BxPC3).MUC5AC was found to express in more than 80% of pancreatic ductal carcinoma specimens. Next we observed that both of si-SW1990 and si-BxPC3 showed significantly lower adhesion and invasion to extracellular matrix components compared with parental cell lines. Expression of genes associated with adhesion and invasion including several integerins, matrix metalloproteinase (MMP) -3 and vascular endothelial growth factor (VEGF) were down-regulated in both MUC5AC suppressed cells. Furthermore, production of VEGF and phosphorylation of VEGFR-1 were significantly reduced by MUC5AC down regulation. Both of si-SW1990 and si-BxPC3 attenuated activation of Erk1/2. In vivo, si-SW1990 did not establish subcutaneous tumor in nude mice.Knockdown of MUC5AC reduced the ability of pancreatic cancer cells to adhesion and invasion, suggesting that MUC5AC might contribute to the invasive motility of pancreatic cancer cells by enhancing the expression of integrins, MMP-3, VEGF and activating Erk pathway.Pancreatic cancer has a poor prognosis; the 5-year survival rate in only 3% and the median survival rate is only 6 months[1]. It is also associated with aggressive cancer cells, and metastatic disease that results from a lack of early-stage diagnostic methods and effective therapies. Adhesiveness and invasiveness of cancer cells play a central role in pancreatic cancer progression [2,3]. Mucins are highly glycosylated glycoproteins that are the major components of the viscous mucous gel covering the surface of epithelial tissues [4]. Changes in mucin expression or glycosylation accompany the development of cancer and influen
Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC  [PDF]
XueLiang Guo, Rhonda G. Pace, Jaclyn R. Stonebraker, Clayton W. Commander, Anthony T. Dang, Mitchell L. Drumm, Ann Harris, Fei Zou, Dallas M. Swallow, Fred A. Wright, Wanda K. O'Neal, Michael R. Knowles
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025452
Abstract: Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10?4 after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.
水通道蛋白5对PMA诱导的原代小鼠气道上皮细胞MUC5AC合成的影响  [PDF]
沈瑶,白春学,陈智鸿
复旦学报(医学版) , 2012, DOI: 10.3969/j.issn.1672-8467.2012.03.002
Abstract: 目的探讨水通道蛋白5(aquaporin5,AQP5)对卟啉醇肉豆蔻酸乙酸酯(phorbolmyristateacetate,PMA)诱导的原代培养小鼠气道上皮细胞MUC5AC合成的影响及可能机制。方法原代培养两种小鼠(AQP5基因敲除鼠和野生鼠)气道上皮细胞,Transwell建立气液平面,2周后扫描电镜及角蛋白免疫组化鉴定气道上皮细胞。蛋白激酶(proteinkinaseC,PKC)特异性激动剂PMA刺激原代小鼠气道上皮细胞及PKC通路特异性阻断剂Calphostinc阻断该通路,ELISA检测两组小鼠MUC5AC蛋白水平的变化,用Westernblot检测小鼠气道上皮细胞PMA刺激后PKC、p-PKC、p-p38、p38、ERK、p-ERK的表达差异。结果气液平面培养后,扫描电镜显示培养的细胞上皮有微绒毛和纤毛覆盖,细胞角蛋白14免疫组化染色为阳性。PMA20ng/mL刺激24h后,两组小鼠气道上皮细胞分泌的MUC5AC明显升高,AQP5基因敲除鼠增加更显著(P<0.05),两者差异有统计学意义。PKC特异性阻断剂Calphostinc能阻断PMA引起的两组小鼠MUC5AC分泌。原代小鼠气道上皮细胞经PMA刺激后,Westernblot检测显示PKC、p38磷酸化激活,ERK通路无变化。结论AQP5通过PKC-p38信号通路影响黏蛋白MUC5AC的合成和分泌。
Polysaccharides and mucin 5AC (MUC5AC) expression in gallbladder mucosa of young patients with gallstones as evaluated by spatial visualization and quantification  [PDF]
Aldona Kasprzak,Wojciech Malkowski,Celina Helak-£apaj,Agnieszka Seraszek
Folia Histochemica et Cytobiologica , 2010,
Abstract: The study aimed at examination of tissue expression of polysaccharides and secretory mucin 5AC (MUC5AC)in young patients (up to 25 years of age) with a symptomatic gallstones. For comparison, patients most frequently subjectedto cholecystectomy were studied, i.e. patients of approximately 50 years of age with the same diagnosis. In quantitativestudies on tissue expression of both mucus components, the modern technique of spatial visualization was applied for thefirst time. Application of the technique permitted to demonstrate significant positive relationships between expression ofglycoproteins (immunocytochemical ABC technique for detection of MUC5AC) and expression of sugar components inmucus (PAS technique) and to confirm suitability of the technique for quantitative appraisal of both histochemical andimmunocytochemical reactions. An even higher expression of polysaccharides in the entire mucosa and of MUC5AC wasdetected in gallbladder epithelium of 50-year-old patients, as compared to young patients with symptomatic gallstones. Inthe young patients, expression of polysaccharides correlated with inflammatory activity (grading), width of gallbladder walland PLT level in peripheral blood. A significantly higher expression of polysaccharides in gallbladder epithelium wasdemonstrated in young patients admitted in the emergency mode to the hospital. These correlations in young patients maysuggest a role of both mucus components in pathogenesis of cholelithiasis in this age group. A quantitative appraisal ofmucus component expression in the two parts of gallbladder mucosa (epithelium vs. entire mucosa) using spatial visualizationtechnique permitted to more accurately compare production of glycoproteins and of polysaccharides in patients withcholelithiasis and to demonstrate additional correlations of a potential clinical significance.
Polysaccharides and mucin 5AC (MUC5AC) expression in gallbladder mucosa of young patients with gallstones as evaluated by spatial visualization and quantification.  [cached]
Aldona Kasprzak,Wojciech Malkowski,Celina Helak-?apaj,Agnieszka Seraszek
Folia Histochemica et Cytobiologica , 2011, DOI: 10.5603/4179
Abstract: The study aimed at examination of tissue expression of polysaccharides and secretory mucin 5AC (MUC5AC) in young patients (up to 25 years of age) with a symptomatic gallstones. For comparison, patients most frequently subjected to cholecystectomy were studied, i.e. patients of approximately 50 years of age with the same diagnosis. In quantitative studies on tissue expression of both mucus components, the modern technique of spatial visualization was applied for the first time. Application of the technique permitted to demonstrate significant positive relationships between expression of glycoproteins (immunocytochemical ABC technique for detection of MUC5AC) and expression of sugar components in mucus (PAS technique) and to confirm suitability of the technique for quantitative appraisal of both histochemical and immunocytochemical reactions. An even higher expression of polysaccharides in the entire mucosa and of MUC5AC was detected in gallbladder epithelium of 50-year-old patients, as compared to young patients with symptomatic gallstones. In the young patients, expression of polysaccharides correlated with inflammatory activity (grading), width of gallbladder wall and PLT level in peripheral blood. A significantly higher expression of polysaccharides in gallbladder epithelium was demonstrated in young patients admitted in the emergency mode to the hospital. These correlations in young patients may suggest a role of both mucus components in pathogenesis of cholelithiasis in this age group. A quantitative appraisal of mucus component expression in the two parts of gallbladder mucosa (epithelium vs. entire mucosa) using spatial visualization technique permitted to more accurately compare production of glycoproteins and of polysaccharides in patients with cholelithiasis and to demonstrate additional correlations of a potential clinical significance.
Regulation of MUC5AC mucin production by the cell attachment dependent pathway involving integrin β1 in NCI-H292 human lung epithelial cells  [PDF]
Jun Iwashita, Kaori Hongo, Yuho Ito, Tatsuya Abe, Jun Murata
Advances in Biological Chemistry (ABC) , 2013, DOI: 10.4236/abc.2013.31001
Abstract:

Mucus hypersecretion in airways is a common pathological change observed in chronic inflammatory diseases and asthma. We investigated the new role of cell attachment to the extracellular matrix (ECM) on the production of the airway mucus protein, MUC5AC mucin, in human airway epithelial cells, NCI-H292. MUC5AC levels of cells cultured on low adhesion plates were 10-fold higher than those of cells cultured on adhesion plates. Cells cultured on bovine serum albumin (BSA) coated plates, which produce low adhesion conditions, also induced the up-regulation of MUC5AC. Mucin staining by PAS and MUC5AC immunodetection confirmed that mucin proteins were overproduced under low adhesion conditions. The major adhesion molecule between cells and the ECM was integrins. A time-course experiment showed that the expression patterns of integrin β1 and MUC5AC protein were inversely proportional. The inhibition of integrin β1 induced an increase in MUC5AC production in cells cultured under adhesion conditions, but not under low adhesion conditions. These results suggested that cell attachment regulates MUC5AC production, which is up-regulated by low adhesion to the ECM, and MUC5AC production is inversely proportional to the function of integrin β1.

Enhanced PKCδ and ERK Signaling Mediate Cell Migration of Retinal Pigment Epithelial Cells Synergistically Induced by HGF and EGF  [PDF]
Yu Jung Chen, Rong Kung Tsai, Wen Chen Wu, Ming Shan He, Ying-Hsien Kao, Wen Sheng Wu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044937
Abstract: Proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) are characterized by the development of epi-retinal membranes which may exert a tractional force on retina. A lot of inflammatory growth factors may disturb the local ocular cells such as retinal pigment epithelial (RPE) cells, causing them to migrate and proliferate in the vitreous cavity and ultimately forming the PVR membrane. In this study, the signal pathways mediating cell migration of RPE induced by growth factors were investigated. Hepatocyte growth factor (HGF), epidermal growth factor (EGF) or heparin-binding epidermal growth factor (HB-EGF) induced a greater extent of migration of RPE50 and ARPE19 cells, compared with other growth factors. According to inhibitor studies, migration of RPE cells induced by each growth factor was mediated by protein kinase C (PKC) and ERK (MAPK). Moreover, HGF coupled with EGF or HB-EGF had synergistic effects on cell migration and enhanced activation of PKC and ERK, which were attributed to cross activation of growth factor receptors by heterogeneous ligands. Furthermore, using the shRNA technique, PKCδ was found to be the most important PKC isozyme involved. Finally, vitreous fluids from PVR and PDR patients with high concentration of HGF may induce RPE cell migration in PKCδ- and ERK- dependent manner. In conclusion, migration of RPE cells can be synergistically induced by HGF coupled with HB-EGF or EGF, which were mediated by enhanced PKCδ activation and ERK phosphorylation.
Involvement of MEK, ERK, PKC and GSK3B in Maintaining the Mitotic Spindle  [cached]
Madhavi Kalive,David G. Capco
International Journal of Biology , 2013, DOI: 10.5539/ijb.v5n2p1
Abstract: The MAPK pathway has been implicated in various functions related to cell cycle regulation. MAPKK (MEK) is part of this pathway and the extracellular regulated kinase (ERK) is its known downstream target. Glycogen synthase kinase 3B (GSK3B) and protein kinase C (PKC) also have been implicated in cell cycle regulation due to their association with the centrosomes along with MEK and ERK. In the current study, we tested the effects of inhibiting MEK on the activities of ERK, GSK3B, PKC, and ?-tubulin. Two types of MEK inhibitors were used, a siRNA inhibitor and U0126. The effects of MEK inhibition were tested by immunocytochemistry and confocal analysis, western blotting, RT-PCR analysis and study of cell numbers in M-phase stages. Results from this study indicate that inhibition of MEKdid not inhibit GSK3B and PKC enrichment at the centrosomes. However, the mitotic spindle showed a reduction in the pixel intensity of microtubules and also a reduction in the number of cells in each of the M-phase stages. A peptide activation inhibitor of ERK was used next. Our results indicated a further decrease in mitotic spindle microtubules than what was seen with the MEK inhibitors and an absence of cells in most of the M-phase stages. GSK3B and PKC enrichment were however not inhibited at the centrosomes. Taken together, the kinases GSK3B and PKC may not function as a part of the MAPK pathway to regulate the mitotic spindle.
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